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    Summary
    EudraCT Number:2019-002735-28
    Sponsor's Protocol Code Number:I8F-MC-GPGN
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-06
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-002735-28
    A.3Full title of the trial
    The Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes (SURPASS-CVOT)
    Comparación del efecto de tirzepatida frente al de dulaglutida sobre los acontecimientos cardiovasculares mayores en pacientes con diabetes de tipo 2 (SURPASS-CVOT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Effect of the drug Tirzepatide compared with the drug Dulaglutide on the Cardiovascular Risk in Patients with Type 2 Diabetes
    Comparación del efecto de tirzepatida frente al de dulaglutida sobre los acontecimientos cardiovasculares mayores en pacientes con diabetes de tipo 2
    A.3.2Name or abbreviated title of the trial where available
    SURPASS-CVOT
    SURPASS-CVOT
    A.4.1Sponsor's protocol code numberI8F-MC-GPGN
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLilly S.A.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly Cork Ltd
    B.5.2Functional name of contact pointClinical Trial Registry Office
    B.5.3 Address:
    B.5.3.1Street AddressEastgate Road, Eastgate Business Park, Little island
    B.5.3.2Town/ cityCo. Cork
    B.5.3.3Post code46285
    B.5.3.4CountryIreland
    B.5.4Telephone number34918362958
    B.5.6E-mailensayosclinicos@lilly.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTirzepatide
    D.3.2Product code LY3298176
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTirzepatide
    D.3.9.2Current sponsor codeLY3298176
    D.3.9.4EV Substance CodeSUB198055
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Trulicity
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDulaglutide
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDulaglutide
    D.3.9.1CAS number 923950-08-7
    D.3.9.3Other descriptive nameDulaglutide
    D.3.9.4EV Substance CodeSUB130484
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type 2 diabetes mellitus
    Diabetes mellitus, de tipo 2
    E.1.1.1Medical condition in easily understood language
    Type 2 diabetes mellitus
    Diabetes mellitus, de tipo 2
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10045242
    E.1.2Term Type II diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess efficacy of maximally tolerated tirzepatide dose up to 15 mg QW compared to QW dulaglutide 1.5 mg on time to first occurrence of the composite endpoint of death from CV causes, MI, or stroke (MACE-3) when both are added to standard of care in patients with T2DM and high CV risk.

    Primary analysis will be an assessment of NI of tirzepatide to dulaglutide for MACE-3. After establishing NI, superiority of tirzepatide compared to dulaglutide for MACE-3 will be evaluated.
    Comparar la eficacia de la dosis máxima tolerada de tirzepatida (en una dosis de hasta 15 mg, 1 v/s) con la de 1,5 mg de dulaglutida 1 v/s, desde el punto de vista del tiempo transcurrido hasta la primera ocasión en la que se produzca el criterio compuesto de valoración (muerte por causas CV, infarto de miocardio o accidente cerebrovascular [MACE-3]), cuando ambos fármacos se añaden al tratamiento de referencia en pacientes con DMT2 y riesgo CV alto.
    El análisis principal será la evaluación de la NI de tirzepatida respecto a dulaglutida, desde el punto de vista de los criterios de valoración MACE-3. Una vez que se establezca la NI, se evaluará la superioridad de tirzepatida sobre dulaglutida, desde el punto de vista de los criterios de valoración MACE-3.
    E.2.2Secondary objectives of the trial
    To assess the superiority of tirzepatide up to 15 mg QW compared to dulaglutide 1.5 mg QW for time to death due to any cause, time to CV death, time to first occurrence of MI and time to first occurrence of stroke.
    Evaluar la superioridad de tirzepatida (en una dosis de hasta 15 mg, 1 v/s) sobre dulaglutida en una dosis de 1,5 mg 1 v/s, desde el punto de vista del tiempo transcurrido hasta la muerte por cualquier causa, el tiempo transcurrido hasta la muerte por causas CV, el tiempo transcurrido hasta la primera ocasión en la que se produzca un IM y el tiempo transcurrido hasta la primera ocasión en la que se produzca un accidente cerebrovascular.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] Men or women at least 40 years old with a diagnosis of T2DM (WHO 2019).
    [2] Established CVD, including at least 1 of the following (a-c):
    a. Coronary artery disease (CAD) with EITHER of the following:
    - Documented history of spontaneous MI
    - ≥50% stenosis in 1 or more major coronary arteries, determined by invasive angiography
    - ≥50% stenosis in 2 or more major coronary arteries, determined by computed tomography coronary angiography (CTCA), or
    - History of surgical or percutaneous coronary revascularization procedure;
    b. Cerebrovascular disease – ANY of the following:
    - Documented history of ischemic stroke
    - Carotid arterial disease with ≥50% stenosis, documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography
    - Carotid stenting or surgical revascularization;
    c. Peripheral arterial disease with EITHER of the following:
    - Intermittent claudication and ankle-brachial index <0.9
    - Prior nontraumatic amputation or peripheral vascular procedure (eg, stenting or surgical revascularization), due to peripheral arterial ischemia.
    [3] HbA1c ≥7% (≥53 mmol/mol) and ≤10.5% (≤91.3 mmol/mol) based on central laboratory assessment at screening.
    [4] Body mass index (BMI) ≥25 kg/m2.
    [5] At the time of signing the informed consent: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials.
    [6] In the investigator’s opinion, patients are well motivated, capable, and willing to learn how to self-inject treatment (tirzepatide or dulaglutide), as required for this protocol (visually impaired persons and/or persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject the study drug).
    [7] Patients are capable of giving signed informed consent.
    [1] Pacientes de ambos sexos de al menos 40 años de edad con diagnóstico de DMT2 (OMS 2019).
    [2] Enfermedad cardiovascular confirmada, incluidas al menos 1 de las siguientes (a-c):
    a. Cardiopatía coronaria (CC) con ALGUNA de las características siguientes:
    - Antecedentes documentados de IM espontáneo
    - ≥50 % de estenosis en 1 o más de una arteria coronaria importante, según los resultados de una angiografía traumática
    - ≥50 % de estenosis en 2 o más de dos arterias coronarias importantes, según los resultados de una angiografía coronaria por tomografía computarizada (ACTC)
    - Antecedentes de un procedimiento de revascularización coronaria percutánea o quirúrgica
    b. Enfermedad cerebrovascular con CUALQUIERA de las características siguientes:
    - Antecedentes documentados de accidente cerebrovascular isquémico
    - Arteriopatía carotídea con ≥50 % de estenosis, documentada mediante ecografía carotídea, resonancia magnética nuclear (RMN) o angiografía
    - Endoprótesis carotídea o revascularización quirúrgica
    c. Arteriopatía periférica con ALGUNA de las características siguientes:
    - Claudicación intermitente e índice tobillo-brazo <0,9
    - Amputación atraumática o procedimiento vascular periférico previos (por ej., endoprótesis o revascularización quirúrgica) por la presencia de isquemia arterial periférica.
    [3] HbA1c ≥7 % (≥53 mmol/mol) y ≤10,5 % (≤91,3 mmol/mol), según los resultados de una prueba realizada durante la selección en el laboratorio central.
    [4] Índice de masa corporal (IMC) ≥25 kg/m2.
    [5] En el momento de la firma del consentimiento informado: Las medidas anticonceptivas que utilicen los pacientes de ambos sexos deben ser coherentes con la normativa local relativa al uso de estas medidas durante la participación en un estudio clínico. 6) Según el criterio del investigador, el paciente está motivado, es capaz y está dispuesto a aprender cómo inyectarse el tratamiento (tirzepatida o dulaglutida), según el protocolo (las personas con discapacidad visual o con otras limitaciones físicas que no puedan administrarse las inyecciones deberán contar con la asistencia de una persona que esté entrenada en la administración de inyecciones del fármaco del estudio).
    [7] El paciente es capaz de proporcionar y firmar el consentimiento informado.
    E.4Principal exclusion criteria
    [8] Have type 1 diabetes mellitus.
    [9] Have uncontrolled diabetes requiring immediate therapy (such as diabetic ketoacidosis) at screening or randomization, in the judgment of the physician.
    [10] Have had 1 or more events of severe hypoglycemia and/or 1 or more events of hypoglycemia unawareness within 6 months prior to screening.
    [11] Have a history of proliferative retinopathy or macular edema. A dilated fundoscopic exam, evaluated by an eye care professional (ophthalmologist or optometrist) is required to confirm eligibility. In addition, nonproliferative diabetic retinopathy that requires acute treatment according to the opinion of the investigator is also excluded.
    [12] Have been hospitalized for CHF within 2 months prior to screening.
    [13] Have chronic New York Heart Association Functional Classification IV CHF.
    [14] Are currently planning a coronary, carotid, or peripheral artery revascularization.
    [15] Had chronic or acute pancreatitis any time prior to screening, irrespective of etiology.
    [16] Have a known clinically significant gastric emptying abnormality (eg, severe diabetic gastroparesis or gastric outlet obstruction), have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery (eg, Lap-Band®, vertical sleeve gastrectomy), or chronically take drugs that directly affect GI motility.
    [17] Have acute or chronic hepatitis, signs or symptoms of any other liver disease, or an alanine aminotransferase (ALT) level ≥3X the upper limit of normal (ULN) for the reference range, as determined by the central laboratory.
    [18] Have known chronic severe renal failure (defined as a known eGFR <15 mL/minute/1.73 m2) or are on chronic dialysis.
    [19] Have evidence of a significant, uncontrolled endocrine abnormality (eg, thyrotoxicosis or adrenal crises).
    [20] Have a family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (MTC) or personal history of nonfamilial MTC.
    [21] Have a serum calcitonin level at screening of: (based on central laboratory results)
    - ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2, or
    - ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2.
    [22] Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years. An exception for this criterion is basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer.
    [23] Have a history of any other condition (such as known drug or alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, may preclude the patient from following and completing the protocol.
    [24] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an organ transplant.
    [25] Have any other condition (eg, hypersensitivity) that is a contraindication to any incretin or GLP-1 RAs.
    [26] Have had an MI, surgical or percutaneous coronary revascularization procedure, ischemic stroke, carotid stenting or surgical revascularization, nontraumatic amputation or peripheral vascular procedure (eg, stenting or surgical revascularization) less than 60 days prior to screening.
    [27] Have had coronary artery bypass graft surgery less than 5 years prior to Screening.
    [28] Treatment with any incretin, GLP-1 RA, or pramlintide in a period of 3 months prior to Visit 1.
    [29] Discontinuation of any incretin, GLP-1 RA, or pramlintide due to intolerability any time prior to Visit 1.
    [30] Patients on intensified insulin regimens or on different combinations of basal and prandial insulins (basal-bolus regimens) who are not able or do not agree to immediately and completely discontinue from all prandial insulin components at randomization are excluded.
    [31] Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
    [32] Have participated within the last 30 days in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
    [33] Have previously completed or withdrawn from this study or randomized into any other study investigating tirzepatide.
    [8] Presentar diabetes mellitus de tipo 1.
    [9] Según el criterio del médico, presentar durante la selección o la aleatorización diabetes sin controlar que requiera tratamiento inmediato (ej., cetoacidosis diabética).
    [10] Haber sufrido ≥1 episodio de hipoglucemia grave o ≥1 episodio de insensibilidad a la hipoglucemia en los 6m anteriores a la selección.
    [11] Antecedentes de retinopatía proliferativa o edema macular. Un oftalmólogo u optometrista deberá realizar una exploración oftalmoscópica con las pupilas dilatadas para confirmar la idoneidad del paciente. También se excluirá a los pacientes con retinopatía diabética no proliferativa que requiera tratamiento urgente según el criterio del investigador.
    [12] Haber sido hospitalizado en los 2m anteriores a la selección por presentar insuficiencia cardíaca congestiva .
    [13] Presentar ICC clase IV según la NY Heart Association.
    [14] Tener programada una revascularización coronaria, carotídea o de una arteria periférica.
    [15] Haber sufrido pancreatitis crónica o aguda antes de la selección, independientemente de su causa.
    [16] Presentar vaciamiento gástrico anómalo con trascendencia clínica (por ej., gastroparesia diabética grave o anismo), haberse sometido a cirugía bariátrica (derivación gástrica) o a cirugía bariátrica restrictiva (por ej., Lap-Band®, gastrectomía vertical) o haber tomado de forma prolongada fármacos que afecten directamente la movilidad gastrointestinal.
    [17] Presentar hepatitis aguda o crónica, o signos o síntomas de una enfermedad hepática, o una concentración de alanina aminotransferasa (ALT) ≥ 3 veces el límite superior de la normalidad (LSN) para el intervalo de referencia, según los análisis en el laboratorio central.
    [18] Presentar insuficiencia renal crónica grave (esto es, una FGe <15 ml/min/1,73 m2) o estar sometiéndose a diálisis durante un período prolongado.
    [19] Presentar indicios de una alteración endocrina importante sin controlar (por ej., tirotoxicosis o insuficiencia suprarrenal aguda).
    [20] Antecedentes personales o familiares de neoplasia endocrina múltiple de tipo 2 (MEN2), antecedentes familiares de carcinoma medular de tiroides (CMT) o antecedentes personales (no familiares) de CMT.
    [21] Presentar durante la selección (según los resultados del laboratorio central) una concentración sérica de calcitonina de:
    - ≥20 ng/l en la visita 1, si la FGe ≥60 ml/min/1,73 m2, o
    - ≥35 ng/l en la visita 1, si la FGe <60 ml/min/1,73 m2.
    [22] Antecedentes de una neoplasia maligna activa o sin tratar, o estar en remisión de una neoplasia maligna clínicamente importante durante un período inferior a 5 años, salvo los casos de carcinoma basocelular o carcinoma epidermoide de la piel, carcinoma in situ del cuello uterino o cáncer de próstata in situ.
    [23] Presentar antecedentes de otra enfermedad (incluidas las toxicomanías, el alcoholismo o las enfermedades psiquiátricas) que, en opinión del investigador, impidan que el paciente siga y complete el protocolo.
    [24] Haberse sometido a un trasplante de órgano (se permiten los de córnea [queratoplastia]) o tener previsto someterse a uno.
    [25] Presentar otra enfermedad (ej., hipersensibilidad) que constituya una contraindicación para la administración de incretinas o AR del GLP-1.
    [26] Haber sufrido un IM o un accidente cerebrovascular isquémico, o haberse sometido a un procedimiento de revascularización coronaria percutánea o quirúrgica o a una revascularización quirúrgica o a la colocación de una endoprótesis carotídea, o que se le haya realizado una amputación atraumática o procedimiento vascular periférico (ej., colocación de una endoprótesis o revascularización quirúrgica) menos de 60 días antes de la selección.
    [27] Haberse sometido a una revascularización coronaria menos de 5 años antes de la selección.
    [28] Haber recibido tratamiento con incretinas, AR del GLP-1 o con pramlintida en los 3m anteriores a la visita 1.
    [29] Haber dejado de tomar incretinas, AR del GLP-1 o pramlintida antes de la visita 1 por presentar intolerabilidad.
    [30] Se excluirá a los pacientes que reciban tratamiento intensivo con insulina o diferentes combinaciones de insulinas basal y prandial (tratamientos basal-bolo) y que en la aleatorización no puedan o no estén de acuerdo en dejar de tomar completa e inmediatamente todas las insulinas prandiales.
    [31] Participar en la actualidad en otro ensayo clínico con un producto en fase de investigación o en otra investigación médica incompatible con el estudio, desde un punto de vista científico o médico.
    [32] Haber participado en los 30 últimos días en un ensayo clínico con un producto en fase de investigación. Si el producto en fase de investigación administrado tiene una semivida prolongada, deberán haber transcurrido 3 meses o 5 semividas (lo que sea mayor).
    [33] Haber finalizado o haber interrumpido previamente la participación en este estudio o haber sido aleatorizado en cualquier otro estudio en el que se investigue tirzepatida.
    E.5 End points
    E.5.1Primary end point(s)
    Time to first occurrence of a component event of a MACE-3.
    Tiempo transcurrido hasta la primera ocasión en la que se produzca uno de los acontecimientos del criterio MACE-3.
    E.5.1.1Timepoint(s) of evaluation of this end point
    An independent CEC will adjudicate all primary endpoint events.
    The primary endpoint is the time from randomization to first occurrence of CEC-confirmed CV death, MI, or stroke.
    Patients will be followed until approximately 1615 patients experience at least 1 component of the primary composite endpoint of CV death, MI, or stroke.
    Un comité de criterios clínicos de valoración (CCCV) independiente validará todos los acontecimientos relacionados con el criterio principal de valoración.
    El criterio principal de valoración es el tiempo transcurrido entre la aleatorización y la primera ocasión en la que se produzca la muerte por causas CV (confirmada por el CCCV), un infarto de miocardio o un accidente cerebrovascular.
    Se realizará seguimiento de los pacientes hasta que aproximadamente 1615 pacientes hayan sufrido al menos 1 de los acontecimientos del criterio principal compuesto de valoración (esto es, muerte por causas cardiovasculares, infarto de miocardio o accidente cerebrovascular).
    E.5.2Secondary end point(s)
    Key Secondary efficacy measures are:
    • Time to death due to any cause;
    • Time to CV death;
    • Time to first occurrence of MI;
    • Time to first occurrence of stroke.

    Additional secondary measures are:
    • Proportion of patients with more than 10% weight loss from screening after 36 months;
    • Change from baseline in:
    o weight, BMI, and waist circumference
    o HbA1c
    o urinary albumin to creatinine ratio
    o blood lipids: total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides;
    • Time to first occurrence of:
    o coronary, carotid, or peripheral revascularizations, individually and as composite
    o hospitalization due to unstable angina
    o composite endpoint of new or worsening nephropathy
    o expanded composite CV outcome, defined as either CV death, MI, stroke, coronary revascularization, hospitalization for unstable angina;
    • Cumulative number of primary composite events of CV death and total (first and recurrent) MI and/or stroke;
    • Cumulative number of CV deaths and total (first and recurrent) HF events requiring hospitalization and/or urgent HF visits.

    Maximally tolerated tirzepatide dose will be measured based on:
    • Incidence of TEAEs and permanent discontinuation of study drug due to AEs
    • Incidence of:
    o pancreatitis
    o severe gastrointestinal events
    o any malignancy (including medullary and papillary thyroid cancers)
    o severe hypoglycemic events
    o immune-mediated reactions including serious allergic and hypersensitivity reactions
    o hepatobiliary events (eg, acute cholecystitis, acute cholelithiasis and drug-induced liver injury)
    o acute renal failure or exacerbation of chronic renal failure
    o diabetic retinopathy complications
    o supraventricular arrhythmias and cardiac conduction disorders
    • Mean change from baseline:
    o blood pressure and pulse rate
    o lipase
    o pancreatic amylase
    o calcitonin
    o eGFR.

    The effects of add-on therapy with up to 15 mg tirzepatide compared to dulaglutide 1.5 mg will be measured based on:
    • Change of antihyperglycemic drugs
    • Patient-reported outcome
    o APPADL
    o IW-SP
    o EQ-5D-5L
    • Time to initiation of insulin of more than 3 months duration for those patients not treated with insulin at study start
    • eGFR from Cystatin-C.
    Los principales criterios secundarios de valoración de la eficacia son:
    • El tiempo transcurrido hasta la muerte por cualquier causa
    • El tiempo transcurrido hasta la muerte por causas CV
    • El tiempo transcurrido hasta la primera ocasión en la que se produzca un IM
    • El tiempo transcurrido hasta la primera ocasión en la que se produzca un accidente cerebrovascular.
    Otros criterios secundarios de valoración son:
    • La proporción de pacientes que hayan experimentado una pérdida de peso superior al 10 % entre el período de selección y el mes 36;
    • La variación respecto al período inicial en:
    o el peso, el IMC y el perímetro de la cintura
    o la concentración de HbA1c
    o el cociente albúmina/creatinina en una muestra de orina
    o la concentración sanguínea de lípidos: colesterol total, colesterol HDL, colesterol LDL y triglicéridos;
    • El tiempo transcurrido hasta la primera ocasión en la que se produzca:
    o una revascularización coronaria, carotídea o periférica, tanto de forma individual como de forma combinada
    o la hospitalización por angina de pecho inestable
    o el criterio de valoración compuesto de una nefropatía nueva o el empeoramiento de una ya existente
    o el criterio compuesto ampliado de valoración de los acontecimientos CV, es decir, los casos de muerte por causas CV, IM, accidente cerebrovascular, revascularización coronaria u hospitalización por angina de pecho inestable;
    • El número acumulado de casos de muerte por causas CV y los casos totales (de primera aparición y recurrentes) de acontecimientos de IM y accidentes cerebrovasculares (criterio principal compuesto de valoración);
    • El número acumulado de casos de muerte por causas CV y los casos totales (de primera aparición y recurrentes) de insuficiencia cardíaca que requiera la hospitalización o la visita al servicio de urgencias.
    La dosis máxima tolerada de tirzepatida se medirá según:
    • La Incidencia de AAT y de los casos de interrupción permanente de la administración del fármaco del estudio por la presencia de AA
    • La incidencia de:
    o pancreatitis
    o acontecimientos gastrointestinales graves
    o cualquier neoplasia maligna (incluidos el cáncer medular de tiroides y el cáncer papilar tiroideo)
    o episodios hipoglucémicos graves
    o reacciones relacionadas con el sistema inmunitario, incluidas las reacciones alérgicas y de hipersensibilidad graves
    o acontecimientos hepatobiliares (por ej., colecistitis aguda, colelitiasis aguda y lesión hepática medicamentosa)
    o insuficiencia renal aguda o exacerbación de la insuficiencia renal crónica
    o complicaciones de la retinopatía diabética
    o arritmias supraventriculares y trastornos de la conducción cardíaca
    • Media de la variación respecto al período inicial en:
    o la tensión arterial y la frecuencia de pulso
    o la lipasa
    o la amilasa pancreática
    o la calcitonina
    o la FGe
    Los efectos del tratamiento de adición con hasta 15 mg de tirzepatida, comparado con los de 1,5 mg de dulaglutida, se medirán en función de:
    • Los cambios en los fármacos antihiperglucémicos.
    • Los resultados percibidos por el paciente
    o el cuestionario APPADL
    o el cuestionario IW-SP
    o el cuestionario EQ-5D-5L
    • El tiempo transcurrido hasta el inicio de la administración de insulina durante más de 3 meses, en aquellos pacientes que no estuvieran recibiendo insulina al inicio del estudio.
    • La FGe según la concentración de cistatina-C.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary outcomes include various glycemic, body weight/composition, renal, biochemical, and health outcome endpoints relevant to the study population.
    Los criterios secundarios de valoración incluyen distintos criterios de valoración de la glucemia, el peso/la composición corporal, la función renal, los parámetros bioquímicos y la salud, pertinentes para la población del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Health Economics
    Economía de la salud
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Dulaglutide
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA241
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    France
    Germany
    Greece
    Hungary
    India
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Poland
    Romania
    Russian Federation
    Slovakia
    Spain
    Sweden
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of the study is the date of the last visit or last scheduled procedure shown in the protocol for the last patient.
    El fin del ensayo es la fecha de la última visita o el último procedimento programado que aparace en el protocolo para el último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days14
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6250
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state0
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4582
    F.4.2.2In the whole clinical trial 12500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None.
    Neither tirzepatide nor dulaglutide will be made available to patients after their participation in the study has ended.
    The patient’s physician(s) will manage the treatment plan as clinically indicated in accordance with local standard of care.
    Una vez que los pacientes dejen de participar en el estudio, no tendrán acceso ni a tirzepatida ni a dulaglutida.
    El médico del paciente elaborará el plan de tratamiento según esté clínicamente indicado, de forma coherente con la atención médica local.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-25
    P. End of Trial
    P.End of Trial StatusOngoing
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